The use of a transdermal drug delivery system as a means for administering therapeutically effective amounts of an active agent is well known in the art. Transdermal devices or systems can be categorized in many different ways, but those commonly called transdermal patches, incorporate the active agent into a carrier, usually a polymeric and/or a pressure-sensitive adhesive formulation.
Many factors influence the design and performance of such drug delivery devices, such as the individual drugs themselves, the physical/chemical characteristics of the system's components themselves and their performance/behavior relative to other system components once combined, external/environmental conditions during manufacturing and storage thereafter, the properties of the topical site of application, the desired rate of drug delivery and onset, the drug delivery profile, and the intended duration of delivery. Cost, appearance, size and ease of manufacturing are also important considerations. The ability to deliver a therapeutically effective amount of the drug in accordance with the intended therapy or treatment is the goal.
The simplest in design is one in which the drug is incorporated into a pressure-sensitive adhesive carrier layer, each surface of which is affixed to a polymeric film/layer—one serving as the backing (to anchor the carrier layer and control passage of environmental influences in and system components out during use) and the other serving as a removable liner (to protect the carrier layer prior to use but removed upon topical application of the carrier layer). However, when addressing all the design and performance factors and considerations to achieve the goal, this system alone cannot always provide the best method.
In this regard, a drug's delivery rate is affected by its degree of saturation and solubility in the carrier composition. Depending on the active agent itself or the dosage necessary to be therapeutically effective, the amount of drug needed to be incorporated into a single, adhesive carrier or matrix composition (i.e., drug loading) can adversely affect or be adversely affected by, such carrier or matrix.
Drug carrier compositions typically require one or more processing solvents, usually organic solvents, in which to incorporate the active agent and/or allow the polymeric/adhesive carrier to be more easily coated onto a backing or release liner. Removal of such solvents is necessary for avoiding problems associated with residual solvent amounts, such as irritation at the topical site of application, drug degradation, drug instability, loss of adhesive or cohesive properties impacting attachment of the system to the user and loss of desired delivery amount or rate. Solvent removal requires that elevated temperatures be applied to the carrier composition to evaporate such solvents. But at the same time, removal of solvents by use of elevated temperatures can also remove or evaporate other desirable components, such as the active agent and drug permeation enhancers. Their loss can even occur at temperatures below which such components may otherwise volatilize by virtue of their interaction with each other and with the other carrier components (relative volalitility or reactivity).
This is particularly problematic for drugs that are controlled substances (for which the Food and Drug Administration requires strict accounting for during the manufacturing process) and/or drugs that have relatively low boiling or melting points, such as low molecular weight drugs and drugs in their free base form.
Another problem often encountered with low molecular weight drugs, particularly those that are liquid at or near room temperature, is the plasticizing effect that such drugs have on the carrier polymers in the transdermal drug delivery system. Namely, the composition becomes “leggy or gummy” resulting in sufficient loss of adhesive and/or cohesive properties and therefore unsuitable for sticking to the skin or mucosa of the user. While using low drug concentrations may decrease the deleterious affects to the carrier's adhesive or cohesive properties, low concentration can result in difficulties in achieving an acceptable delivery rate and the drug may still be lost during processing. Similarly, increasing polymer concentrations by increasing thickness or surface area of the carrier composition provides little flexibility in effectively controlling the release rate of a variety of drugs. It would therefore be worthwhile to provide a transdermal delivery system, which allows the adhesive characteristics to be maintained in the drug-containing layer while providing desired control of delivery rate and profile of the system.
Formulating with low molecular weight drugs that are liquid at or near room temperatures is further particularly difficult in adhesive carrier layer compositions because such drugs more readily or easily permeate skin or mucosa. Such systems often cannot be adequately optimized to control onset of delivery (i.e., slow down or retard) and/or maintain delivery for an extended duration of delivery without compromising other design and performance factors and considerations.
With respect to d-amphetamine in free base form, a particularly preferred low molecular weight drug that is liquid at or near room temperatures, multiple concerns arise when manufacturing with processing solvents. The drug is volatile at room temperature. The drug degrades in the presence of certain solvents, particularly ethyl acetate. The drug degrades into the carbonate form in the presence of carbon dioxide commonly found in atmospheric air. Accordingly, manufacturing a transdermal system using processing solvents and effectively deliver such a drug is even more problematic.
Additionally, transdermal carrier compositions based on acrylic pressure-sensitive adhesive polymers are often preferred for their ability to incorporate or solubilize many drugs. In order to provide for adequate wear properties and drug release from the composition, acrylic-based pressure-sensitive adhesives are typically polymerized with functional monomers to provide functional groups on the acrylic-based adhesive. A problem associated with the use of such acrylic-based polymers with functional groups is that due to the generally high solubility of the drug, a large amount of drug generally must be incorporated into the composition to saturate it and provide an adequate drug release to the skin of the user. In use with low molecular weight drugs or controlled substances, the loss of the drug in the manufacturing process again can be a significant problem.
Attempts have been made to utilize rate controlling membranes and/or multiple layers, and to dissolve or suspend certain drugs in thermoplastic type carrier compositions without the use of solvents. These drug delivery devices generally do not allow a great amount of flexibility in effectively controlling the release rate of a variety of drugs, which in turn also severely limits their therapeutic application, and are expensive or burdensome to manufacture. Moreover, multiple adhesive layers are often required to affix the other layers or membranes to each other, and/or to the site of topical application.
Thus, it would therefore be desirable to provide a system for use with many types of drugs, in which the permeation rate and profile can be easily adjusted while providing an active agent-containing carrier composition formulated in a simple and cost effective manner. It would be further advantageous to avoid drug loss encountered in manufacturing methods requiring high temperature heating or drying after addition of a drug to the carrier composition.